Angiotensin II antagonists for the treatment of viral diseases

Abstract: An angiotensin II antagonist compound is administered to mammals with viral disease. This administration ameliorates virus-associated cell injuries, producing therapeutic effects in viral diseases. This compound is also useful for the prevention of such diseases.

Description: Industrial Field of Utilization The present invention relates to pharmaceutical composition for viral diseases which comprises an angiotensin II antagonist compound as an active ingredient. Prior Art Virus vaccines are chiefly used in the prevention of viral diseases but each vaccine is specific and effective only for the corresponding virus. While there exist many kinds of viruses, vaccines commercially available today are limited in kind. Furthermore, each virus has many mutants and it is often the case that a vaccine is not effective for all strains of the same virus. It is also a very difficult task to develop vaccines with low risks of side effects. Meanwhile, a variety of antiviral drugs (aciclovir, ganciclovir, Ala-A, etc.) have been developed and clinically in use but they are effective only for very limited types of viral infections and no drug is available that is effective for a variety of viral diseases. Moreover, the administration of such antiviral drugs may entail severe adverse reactions prohibiting clinical application. In recent years, interferons have come to be used in the treatment of some diseases inclusive of viral hepatitis but side effects inclusive of fever have been reported with high frequencies. Moreover, while interferons do actually inhibit the proliferation of viruses, there is no report suggesting that they directly protect the cells from damages. Gamma-globulin is prevalently used in the treatment of viral diseases but clinical responses are not necessarily constant and definite. It is disclosed in Supplement to the Journal of the American College of Cardiology, Vol. 21 (2), February, 1993, Page 197a that the angiotensin II antagonist losartan was tested in the treatment of viral myocarditis in mice. However, it was found that only an extremely high dosis of losartan was effective and that other compounds such as captopril are much more effective for treating viral myocarditis in mice. Problems that the Invention is to Solve Viruses vary a great deal as mentioned above and it is difficult to institute therapies specific to the respective viruses. Therefore, it is an objective of paramount importance to prevent or ameliorate cellular damages in various organs which occur in a variety of viral diseases. It is generally acknowledged that the cell injury in viral diseases includes not only direct damages inflicted by the proliferation of viruses but is associated with various immunologic reactions elicited by infection with viruses. The present invention has for its object to provide a prophylactic/therapeutic regimen for viral diseases which is directed to the prevention and treatment of cell injuries in various organs regardless of the type of virus involved. Summary of the Invention Under the circumstances the inventor of the present invention explored into the domain of prophylactic/therapeutic treatment of viral diseases and found surprisingly that the use of compounds having angiotensin II antagonistic activity results in accomplishment of the above-mentioned object and have brought the present invention into being. Therefore, the present invention provides the use of a compound of the formula (I): wherein R 1 is C 1-5 alkyl which may be substituted by hydroxy, amino, halogen or C 1-4 alkoxy; R 2 is a group of the formula -CO-D, wherein D represents a hydroxyl group or a C 1-4 alkoxy group, the alkyl moiety of which may be substituted by hydroxy, amino, halogen, C 2-7 alkanoyloxy, C 4-9 cycloalkanoyloxy, C 1-6 alkoxycarbonyloxy, C 3-8 cycloalkoxycarbonyloxy, C 1-4 alkoxy or C 3-8 cycloalkoxy; Y is a bond, -O-, -S- or -N(R 4 )- where R 4 is hydrogen or (C 1-4 ) alkyl; A is a benzene ring which may be substituted, in addition to group R 2 , by halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, a group of the formula -CO-D', wherein D' represents a hydroxyl group or a C 1-4 alkoxy group the alkyl moiety of which may be substituted by hydroxy, C 1-4 alkoxy, C 2-6 alkanoyloxy, C 1-6 alkoxycarbonyloxy or cyclohexyloxycarbonyloxy, or an amino group which may be substituted by C 1-4 alkyl; X signifies that the phenylene group and phenyl group are joined to each other either directly or through a spacer comprising a chain of not more than 2 spacer atoms; R 3 is and n is an integer of 1-2; or a salt thereof for the manufacture of a medicament for the treatment or prophylaxis of viral diseases. Detailed Explanation of the Invention The salt mentioned above is a pharmacologically acceptable salt, thus including salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids. The preferred salts with inorganic bases are salts with alkali metals such as the sodium, potassium, etc., salts with alkaline earth metals such as calcium, magnesium, etc., aluminum salt and ammonium salt. The preferred salts with organic bases are salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and so on. The preferred salts with inorganic acids are salts with hydrochloric acid, hydrobromic acid, nitric acid, sufuric acid, phosphoric acid and so on. The preferred salts with organic acids are salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and so on. The preferred salts with basic amino acids are salts with arginine, lysine, ornithine and so on. The preferred salts with acidic amino acids are salts with aspartic acid, glutamic acid and so on. Referring to the above formula (I), the group R 3 which is capable of forming an anion (a group having a hydrogen atom which can be released as a proton) is a 5-membered monocyclic heterocyclic residue of the formula As residue R 3 there are preferably mentioned 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl and 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl. The heterocyclic residue (R 3 ) may exist as tautomers. For example, there are three tautomers a', b' and c' as in The heterocyclyl group of residue R 3 includes all of a', b' and c'. R 3 is also preferably a tetrazolyl group. X signifies that the adjacent phenylene and phenyl groups are coupled either directly or indirectly through a spacer comprising a chain of not more than 2 spacer atoms (preferably directly). This spacer may be any divalent chain whose linear moiety comprises 1 or 2 atoms and may be branched. Thus, lower (C 1-4 ) alkylene groups, -CO-, -O-, -S-, -NH-, -CO-NH-, -O-CH 2 -, -S-CH 2 -, -CH=CH-, etc. can be mentioned. Furthermore, n represents a whole number of 1 or 2 (preferably 1). In the following formulas, R 1 represents a (C 1-5 ) alkyl (more preferably a (C 1-4 ) alkyl) group which may be substituted by hydroxy, amino, halogen or (C 1-4 ) alkoxy and Y is a bond, -O-, -S- or -N(R 4 )- (where R 4 is hydrogen or (C 1-4 ) alkyl). The group R 2 is a group of the formula -CO-D, wherein D represents a hydroxyl group or a (C 1-4 ) alkoxy group the alkyl moiety of which may be substituted by hydroxy, amino, halogen, (C 2-7 )alkanoyloxy (e.g. acetoxy, pivaloyloxy, etc.), (C 4-9 )-cycloalkanoyloxy, (C 1-6 )alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.), (C 3-8 ) cycloalkoxycarbonyloxy, (C 1-4 ) alkoxy or (C 3-8 ) cycloalkoxy. The substituent group R 2 thus includes -COOH and its salt, -COOMe, -COOEt, -COOt-Bu, -COOPr, pivaloyloxymethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyroxymethoxycarbonyl, isobutyroxymethoxycarbonyl, 1-(ethoxycarbonyloxy)ethoxycarbonyl, 1-(acetoxy)ethoxycarbonyl, 1-(isobutyroxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, cyclopentylcarbonyloxymethylcarbonyl and so on. A is a benzene ring which may have substituents in addition to the group represented by R 2 , namely halogen (e.g. F, Cl, Br, etc.), nitro, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, amino which may be substituted by (C 1-4 ) alkyl (e.g. amino, N-(C 1-4 ) alkylamino (e.g. methylamino etc.), or N,N-di(C 1-4 ) alkylamino (e.g. dimethylamino etc.) or a group of the formula -CO-D', wherein D' represents a hydroxyl group or a (C 1-4 ) alkoxy group the alkyl moiety of which may be substituted by hydroxy, (C 1-4 ) alkoxy, (C 2-6 ) alkanoyloxy (e.g. acetoxy, pivaloyloxy, etc.) or (C 1-6 ) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.). The preferred substituents are (C 1-4 ) alkyl and halogen. These substituents may be situated in 1 or 2 optional substitutable positions of the cyclic structure. The compound of formula (I) includes the benzimidazole-7-carboxylic acid compounds and their derivatives described in Japanese published unexamined patent application (Kokai Tokkyo Koho) No. 9373/1992, and 364171/1992, and EP 520423. Particularly preferred are compounds of formula (I) wherein R 1 represents a (C 1-5 ) alkyl group (preferably a (C 1-4 ) alkyl group) which may be substituted by hydroxy, amino, halogen or (C 1-4 ) alkoxy; R 2 represents a group of the formula -CO-D, wherein D represents a hydroxyl group or a (C 1-4 ) alkoxy group the alkyl moiety of which may be substituted by hydroxy, amino, halogen, (C 2-6 ) alkanoyloxy (e.g. acetoxy, pivaloyloxy, etc.), (C 1-6 ) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) or (C 1-4 ) alkoxy; the ring A represents a benzene ring which may be substituted, in addition to group R 2 , by halogen (e.g. F, Cl, Br, etc.), (C 1-4 ) alkyl, (C 1-4 ) alkoxy, nitro, a group of the formula -CO-D', wherein D' represents a hydroxyl group or a (C 1-4 ) alkoxy group the alkyl moiety of which may be substituted by hydroxy, (C 1-4 ) alkoxy, (C 2-6 ) alkanoyloxy (e.g. acetoxy, pivaloyloxy, etc.) or (C 1-6 ) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.), or an amino group which may be substituted by (C 1-4 ) alkyl (preferably a benzene ring substituted by (C 1-4 ) alkyl or halogen, and more preferably a benzene ring having no substituent other than a group of the formula R 2 ); Y represents -N(R 4 )- [wherein R 4 represents hydrogen or (C 1-4 ) alkyl]; R 3 represents a tetrazolyl group; n represents 1; X represents a bond. Angiotensin II antagonist compound used in the present invention include compounds disclosed in the specifications of U.S. Patent No. 5,183,899, EP0425921A1, EP0430300A2, EP0434038A1, EP0442473A1, EP0443568A1, EP0445811A2, EP0459136A1, EP0483683A2, EP0520423A2, EP Application No. 93.114754.0 and EP application No. 93.120135.4. As the preferred compounds for use as the active ingredient in the present invention may be mentioned the compounds described in the examples of Japanese published unexamined patent application (Kokai Tokkyo Koho) No. 364171/1992 or EP0459135A1 and EP 520423A2. In particular, (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, pivaloyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate and 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]-methyl]-1H-benzimidazole-7-carboxylic acid are preferably used as the active ingredient in the present invention. As compounds of formula (I) may be mentioned the compounds disclosed inter alia in Japanese published unexamined patent application (Kokai Tokkyo Koho) No. 9373/1992, Japanese published unexamined patent application (Kokai Tokkyo Koho) No. 364171/1992 and EP 520423 and these compounds can be produced by the processes described in the same patent literature. The compound of formula (I) which is used as the angiotensin II antagonist compound in the present invention is low in toxicity and of value as a prophylactic/therapeutic agent for viral diseases in animals, particularly mammalian animals (such as man, dog, rabbit, mouse, rat, etc.). The viral disease addressed by the present invention includes those diseases which are caused or induced by pathogenic viruses belonging to either the category of DNA viruses or the category of RNA viruses. Examples of such viruses are presented below. DNA viruses: Poxviruses, herpesviruses, adenoviruses, parvoviruses RNA viruses: Revoviruses, togaviruses, coronaviruses, rhabdoviruses, paramyxoviruses, orthomyxoviruses, bunyaviruses, arenaviruses, retroviruses, picornaviruses, caliciviruses The specific viral diseases include viral hepatitis (A, B, C, E), influenza, viral pneumonia, viral bronchitis, herpetic infections (simplex virus, EB virus (infectious mononucleosis), herpes zoster), poliomyelitis, AIDS (HIV infection), adult T-cell leukemia (ATL), papilloma, measles, rubella, exanthema subitum, erythema infectiosum, viral encephalitis, viral myelitis, cytomegalovirus infection, mumps, varicella, rabies, viral enteritis, viral myocarditis, viral pericarditis and so on. Among others, the present invention is preferably applicable for treatment or prevention of diseases which are caused or induced by RNA viruses or hepatitis viruses. There are particularly mentioned orthomyxoviruses or picornaviruses as RNA viruses. In addition, there are particularly mentioned viral hepatitis (A, B, C, E), influenza, viral encephalitis, viral enteritis, viral myocarditis or viral pericarditis among viral diseased described above. The compound of formula (I) or a salt thereof can be administered orally, parenterally, by inhalation, intrarectally or topically. It can be used in the form of a pharmaceutical composition or preparation (e.g. powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixers, suspensions, solutions, etc.) containing at least one species of the compound of the invention in combination with a pharmaceutically acceptable carrier (such as adjuvants, excipients, ointment bases and/or diluents). The composition or preparation for medical use can be manufactured by the conventional procedures. As used in this specification, the term 'parenteral' or 'parenterally' refers to any of the subcutaneous, intravenous, intramuscular, intraperitoneal, drip and other routes or methods of administration. Injectable preparations, for example sterile aqueous or oily suspensions for injection can be manufactured by the procedure well established in the field using an appropriate dispersant or wetting agent and a suspending agent. The sterile injectable preparations may also be sterile solutions or suspensions in water, a nontoxic diluent, solvent or vehicle acceptable for purposes of injection. As examples of said vehicle or solvent may be mentioned water, Ringer's solution, isotonic saline and the like. Moreover, sterile nonvolatile oils can be used as the solvent or suspension vehicle. For such purposes, virtually any type of nonvolatile oil or fatty acid can be used. Thus, natural, synthetic and semisynthetic fatty oils or fatty acids and natural, synthetic and semisynthetic mono-, di- or triglycerides can be mentioned. Suppositories for rectal administration can be manufactured using the active ingredient and a suitable non-irritating base such as cocoa butter, polyethylene glycol and other substances which are solid at room temperature but liquid at the rectal temperature and, as such, would melt in the rectum to release the active ingredient. The solid dosage form for oral administration includes the above-mentioned powders, granules, tablets, pills, capsules and so on. To manufacture such a solid dosage form, the active ingredient compound can be mixed with at least one additive such as sucrose, lactose, cellulose and its derivatives, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectin, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymers and glycerides. Such dosage forms may, as usual, contain further additives, e.g. inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbic acid, etc., antioxidants such as ascorbic acid, α-tocopherol, cysteine, etc., disintegrators, binders, thickeners, buffers, sweeteners, flavorants, perfumes and so on. Tablets and pills may be enteric-coated. The liquid for oral administration includes medicinally acceptable emulsions, syrups, elixirs, suspensions, solutions, etc. which may contain any inert diluent that is routinely used in the field of art, such as water. The dosage for any specific patient or individual is determined according to such parameters as age, body weight, general physical condition, sex, diet, drip time, therapeutic regimen, excretion rate, combination of plural drugs, current stage of disease to be managed and so on. The compound of general formula (I) or a salt thereof is low in toxicity and can be used safely. The daily dose varies with the patient's condition and body weight, species of compound, administration route, etc. but for administration as a therapeutic drug for viral disease in an adult human, it is preferable that a daily oral dose of 0.5 ∼ 20 mg or a daily intravenous dose of 0.5 ∼ 20 mg be administered in a single dose or in 2 or 3 divided doses. Effect of the Invention Administration of an angiotensin II antagonist compound in accordance with the present invention ameliorates virus-associated cell injuries, producing therapeutic effects in viral diseases. It is also useful for the prevention of such diseases. The following test example is intended to demonstrate the biological activity of the angiotensin II antagonist compound and salt. Test Example Effect of angiotensin II antagonist compound in viral myocarditis Compound 1: 1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate Method: Four-week-old DBA/2 mice were divided into 3 groups (n per group = 21) and intraperitoneally inoculated with 10 pfu (plaque forming units) of encephalomyocarditis (EMC) virus. Starting 2 days after inoculation, control 5% gum arabic solution (vehicle) (Group A), Compound 1, 0.3 mg/kg, (Group B) and Compound 1, 3 mg/kg, (Group C) were respectively administered daily until day 14. The survival rates in the respective groups on day 14 were compared by the method of Kaplan-Mayer. In survivals, body weight (BW), heart weight (HW) and heart/body weight ratio (HW/BW) were determined and the histopathological findings of the heart were scored for each of the three parameters of myocardial cell necrosis, cellular infiltration and calcification on the grading scale of 1 (<25%), 2 (25%≤, <50%), 3 (50%≤, <75%) and 4 (75%≤). The above animal model of dilated cardiomyopathy is described in Circulation, 65:1230-1235, 1982 or Circulation, 66:355-360, 1982. The blood angiotensin II level was determined by radioimmunoassay. Intergroup comparison was made by ANOVA test. Results: The survival rates on day 14 were 47.6% in Group A, 47.6% in Group B and 57.1% in Group C. No significant difference was found. The BW, HW and HW/BW data in survivals were as follows. Group BW (g) HW (mg) HW/BW (x 10 3 ) A (n=10) 14.7±2.5 133±33 9.69±4.34 B (n=10) 14.2±2.1 139±28 10.14±3.30 C (n=12) 14.6±2.2 106±24 7.42±1.99 Pathological findings were as follows. Group Myocardial cell necrosis Cellular infiltration Calcification A (n=10) 2.3±1.2 2.6±1.3 2.1±1.1 B (n=10) 1.6±0.5 2.3±0.7 1.6±0.5 C (n=12) 1.1±0.3 1.4±0.7 1.1±0.3 Whereas the mean angiotensin II level in non-infected mice (n=5) was 32 pg/ml, that in infected mice (n=6) was elevated to 73 pg/ml. The above results indicate that, in viral myocarditis, the angiotensin II-receptor antagonist alleviates myocardial damage and suppresses cardiac enlargement following the acute stage. Examples The following examples are intended to describe the invention in further detail and should by no means be construed as defining the scope of the invention. Formulation Examples Prophylactic/therapeutic dosage forms for viral diseases, each containing the angiotensin II antagonist compound of the invention as an active ingredient, can be manufactured according to the following exemplary formulations. 1. Capsules (1) 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg per capsule 180 mg (1), (2), (3) and one-half of (4) are blended and granulated. To the granulation is added the remainder of (4) and the whole composition is sealed into gelatin capsule shells. 2. Tablets (1) 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg per tablet 230 mg (1), (2), (3), 2/3 of (4) and 1/2 of (5) are blended and granulated. To the granulation are added the remainders of (4) and (5) and the whole composition is compression-molded to provide tablets. 3. Injection (1) Disodium 2-methylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate 10 mg (2) Inositol 100 mg (3) Benzyl alcohol 20 mg per ampule 130 mg (1), (2) and (3) are dissolved in sufficient distilled water for injection to make 2 ml and this solution is sealed into ampules. The whole procedure is carried out under sterile conditions. 4. Capsules (1) 1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylate 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg per capsule 180 mg (1), (2), (3) and 1/2 of (4) are blended and granulated. To the granulation is added the remainder of (4) and the whole composition is sealed into gelatin capsule shells. 5. Tablets (1) 1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylate 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg per tablet 230 mg (1), (2), (3), 2/3 of (4) and 1/2 of (5) are blended and granulated. To the granulation are added the remainders of (4) and (5) and the whole composition is compression-molded into tablets. 6. Injection (1) Disodium 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate 10 mg (2) Inositol 100 mg (3) Benzyl alcohol 20 mg per ampule 130 mg (1), (2) and (3) are dissolved in sufficient distilled water for injection to make 2 ml and the solution is sealed into ampules. The whole process is carried out under sterile conditions.

Claims: Use of a compound of the formula (I): wherein R 1 is C 1-5 alkyl which may be substituted by hydroxy, amino, halogen or C 1-4 alkoxy; R 2 is a group of the formula -CO-D, wherein D represents a hydroxyl group or a C 1-4 alkoxy group, the alkyl moiety of which may be substituted by hydroxy, amino, halogen, C 2-7 alkanoyloxy, C 4-9 cycloalkanoyloxy, C 1-6 alkoxycarbonyloxy, C 3-8 cycloalkoxycarbonyloxy, C 1-4 alkoxy or C 3-8 cycloalkoxy; Y is a bond, -O-, -S- or -N(R 4 )- where R 4 is hydrogen or (C 1-4 ) alkyl; A is a benzene ring which may be substituted, in addition to group R 2 , by halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, a group of the formula -CO-D', wherein D' represents a hydroxyl group or a C 1-4 alkoxy group the alkyl moiety of which may be substituted by hydroxy, C 1-4 alkoxy, C 2-6 alkanoyloxy, C 1-6 alkoxycarbonyloxy or cyclohexyloxycarbonyloxy, or an amino group which may be substituted by C 1-4 alkyl; X signifies that the phenylene group and phenyl group are joined to each other either directly or through a spacer comprising a chain of not more than 2 spacer atoms; R 3 is and n is an integer of 1-2; or a salt thereof for the manufacture of a medicament for the treatment or prophylaxis of viral diseases. Use according to claim 1, wherein X is a bond. Use according to claim 1 or 2, wherein R 3 is Use according to claim 1 or 2, wherein R 3 is The use according to claim 3 wherein the compound of formula (I) is (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. The use according to claim 3 wherein the compound of formula (I) is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid. The use according to claim 3 wherein the compound of formula (I) is pivaloyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. The use according to claim 4 wherein the compound of formula (I) is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid. Use of a compound according to any of claims 1 to 8 or a salt thereof for the manufacture of a medicament for ameliorating or preventing cellular damage caused by viruses. The use according to any of claims 1 to 9 wherein the viral diseases are diseases caused or induced by RNA viruses or hepatitis viruses. The use according to claim 10 wherein the RNA viruses are orthomyxoviruses or picornaviruses. The use according to any of claims 1 to 9 wherein the viral diseases are viral hepatitis (A, B, C, E), influenza, viral encephalitis, viral enteritis, viral myocarditis or viral pericarditis.

Inventors: MATSUMORI AKIRA, MATSUMORI, AKIRA
Applicants: MATSUMORI AKIRA, TAKEDA CHEMICAL INDUSTRIES LTD, MATSUMORI, AKIRA, TAKEDA CHEMICAL INDUSTRIES, LTD.
Application year: 1994
Main classification: A61K31
IPC codes: A61K31